Interpreting Divergent Short-Chain Fatty Acid Effects in Alzheimer's Disease: A Seven-Axis Framework.

Abstract

Studies of short-chain fatty acids (SCFAs) in Alzheimer's disease (AD) report protective, neutral, and adverse findings, but the same class label often conceals non-equivalent exposures and endpoints. We propose an AD-specific interpretive framework that organizes this heterogeneity as a causal sequence: source or intervention → SCFA species, dose, and route → absorption and metabolic filtering → target-compartment exposure → host and disease state → responding cell type → endpoint. Seven interdependent axes-SCFA species, dose, route, compartment, exposure context, disease stage, and responding cell type-identify the coordinates needed to compare studies. This organization separates administered dose from achieved exposure, direct entry into the central nervous system from blood-brain barrier or peripheral gut-brain signaling, and stage-related disease biology from evidence of stage-specific treatment efficacy. It also requires symmetric interpretation of null findings according to exposure verification, target engagement, power, cellular resolution, and endpoint specificity. The framework integrates rather than replaces established microbiome, pharmacological, and neuroimmune principles and has not been validated as a predictor of effect direction. Its explanatory value can be tested by prespecified meta-regression, variance partitioning, interaction analysis, matched-exposure replication, and causal mediation. Persistent opposite effects under matched coordinates would indicate missing dimensions or failure of the framework. This Perspective therefore supports mechanism-linked, biomarker-informed research rather than nonspecific SCFA supplementation in unselected patients.